We have shown by 3.5% acrylamide gel electrophoresis that plasma fibrinogen in man is composed of 2 major fractions: a high molecular weight (HMW: 340,000) and a lower molecular weight (LMW: approximately 320,000) fraction. The LMW fraction is believed to be a proteolytic derivative (A alpha chain degraded) of HMW ("native") fibrinogen. However, no enzymatic system, including naturally induced fibrinolytic activity, in blood was found to be responsible for this limited degradation. We therefore postulated an extravascular pathway of fibrinogen degradation and catabolism which we believe is consistent with the rapid first T1/2 of fibrinogen and its large extravascular pool. Preliminary experimental observations are in accord with the existence of a tissue pathway of fibrinogen degradation. Since we have shown that fibrinogen in most mammals is also composed of 2 major clottable protein fractions, the catabolic pathway responsible for this heterogeneity is believed common to many species. The mechanism of limited fibrinogen degradation and fibrinogen catabolism to unclottable derivatives will be investigated in vivo and ex vivo after the injection of purified 125I-HMW fibrinogen and 75Se-methionine. The kinetics of appearance of the radiolabel in the LMW fraction and in the unclottable derivatives in blood and tissues will be determined. The kinetics of appearance of the LMW fraction in blood after defibrination will be studied for comparison to evaluate the role of the liver in fibrinogen degradation. A study of fibrinogen heterogeneity in lymph compared with blood will provide additional information on the tissue pathway. The radioactivity in the tissue of various organs will be isolated and the saline extractable and tissue bound material characterized and compared. The roles of plasminogen activator and transamidating enzymes will be evaluated. The unclottable catabolic derivatives will be isolated from the blood of nephrectomized animals and compared with FDP in order to evaluate differences between fibrinolysis (intravascular) and fibrinolysis (intravascular) and fibrinogenolysis (?extravascular).